title: Transcriptional activation of heat shock protein 90 mediated via a proximal promoter region as trigger of caspofungin resistance in Aspergillus fumigatus.
abstract: Invasive aspergillosis is a deadly infection for which new antifungal therapies are needed. Heat shock protein 90 (Hsp90) is an essential chaperone in Aspergillus fumigatus representing an attractive antifungal target. Using a thiamine-repressible promoter (pthiA), we showed that genetic repression of Hsp90 significantly reduced virulence in a murine model of invasive aspergillosis. Moreover, substituting the A. fumigatus hsp90 promoter with 2 artificial promoters (potef, pthiA) and the Candida albicans hsp90 promoter resulted in hypersensitivity to caspofungin and abolition of the paradoxical effect (resistance at high caspofungin concentrations). By inducing truncations in the hsp90 promoter, we identified a 100-base pair proximal sequence that triggers a significant increase of hsp90 expression (≥1.5-fold) and is essential for the paradoxical effect. Preventing this increase of hsp90 expression was sufficient to abolish the paradoxical effect and therefore optimize the antifungal activity of caspofungin.
authors.affiliation: Division of Pediatric Infectious Diseases, Department of Pediatrics.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Lamoth
authors.forename: Praveen R
authors.initials: PR
authors.lastname: Juvvadi
authors.forename: Christopher
authors.initials: C
authors.lastname: Gehrke
authors.forename: Yohannes G
authors.initials: YG
authors.lastname: Asfaw
authors.forename: William J
authors.initials: WJ
authors.lastname: Steinbach
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001232:Aspergillus fumigatus / Q000187:drug effects* / Q000235:genetics; D000077336:Caspofungin; D004195:Disease Models, Animal; D025141:Drug Resistance, Fungal; D054714:Echinocandins / Q000494:pharmacology* / Q000627:therapeutic use; D018841:HSP90 Heat-Shock Proteins / Q000096:biosynthesis*; D055666:Lipopeptides; D008297:Male; D051379:Mice; D011401:Promoter Regions, Genetic; D055732:Pulmonary Aspergillosis / Q000188:drug therapy / Q000382:microbiology / Q000473:pathology; D015533:Transcriptional Activation
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D018841:HSP90 Heat-Shock Proteins; D055666:Lipopeptides; D000077336:Caspofungin
keywords: antifungal resistance; aspergillus; caspofungin; echinocandin; heat shock protein 90; invasive aspergillosis; paradoxical effect; virulence